Evaluating the effects of hexavalent chromium on uterine vascular remodeling

评估六价铬对子宫血管重塑的影响

• 批准号: 10581242
• 负责人: Sakhila Banu
• 金额: $ 22.78万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10581242
• 关键词: Actins; Adverse effects; Affect; Age; Apoptosis; Area; Arteries; Birth Rate; Blood; Blood Vessels; Carcinogens; Cells; Chemical Exposure; Child; Chromium Compounds; Clinical Data; Collagen; Communities; Complex; Cytokeratin; Data; Databases; Diameter; Disease; Dose; Elastin; Endocrine Disruptors; Endothelial Cells; Endothelium; Environmental Exposure; Euthanasia; Experimental Designs; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Resorption; Fetal Weight; Fetus; Grant; Growth Factor; Health; Heavy Metals; High-Risk Pregnancy; Hospital Records; Human; Individual; Infant; Infertility; Interstitial Collagenase; Invaded; Label; Litter Size; Malignant Neoplasms; Mediating; Michigan; Modeling; Molecular; Newborn Infant; Nutrient; Outcome; Oxidative Stress; PTK2 gene; Pathway interactions; Pattern; Perfusion; Persons; Placenta; Placentation; Potassium; Predisposition; Pregnancy; Pregnancy Outcome; Pregnancy loss; Pregnant Women; Premature Birth; Premature Labor; Proteins; Rattus; Relaxation; Reporting; Role; STAT1 gene; STAT3 gene; Shapes; Signal Pathway; Signaling Molecule; Site; Spiral Artery of the Endometrium; Spontaneous abortion; Stat5 protein; Thick; Time; United States; United States National Institutes of Health; Uterus; Vascular Smooth Muscle; Vascular remodeling; Vulnerable Populations; Woman; abortion; chromium hexavalent ion; contaminated water; early pregnancy; epidemiologic data; experience; experimental group; fetal; human female; immunocytochemistry; indexing; innovation; male; novel; pregnancy disorder; pregnancy health; pregnant; premature; pressure; pup; reproductive; response; spatiotemporal; trophoblast; water quality; working group

PROJECT SUMMARY The United States is one of the world’s leading producers of chromium compounds. According to the National Tap Water quality database and Environmental Working Group report, ~74 million people in the U.S in nearly 7,000 communities drink water contaminated with hexavalent chromium, Cr(VI), and they are predisposed to various health problems including infertility, pre-term labor, pre-mature abortion, intrauterine fetal growth restriction, and cancers. A study was conducted using data released from the hospital records of newborn babies and pregnant women from Willits, CA, exposed to Cr(VI). For the first time, the detrimental reproductive effects from non-occupational Cr(VI) exposure in human females and their infants was reported in the U.S. Our study involving the human placenta reported a positive correlation between Cr accumulation in the term placenta (from Michigan women) and increased oxidative stress. However, how Cr(VI) causes abnormal placental development, and pregnancy disorders is unknown. The uterine spiral artery is extensively remodeled to deliver a sufficient supply of maternal blood and nutrients to the developing fetus. Abnormal uterine spiral artery remodeling adversely affects pregnancy. The current study hypothesizes that Cr(VI) disrupts uterine spiral artery remodeling by inhibiting trophoblast cell invasion and altering growth factor(s)-mediated signaling pathways. For the first time, our preliminary study demonstrates Cr(VI)-induced thickness of uterine artery wall and narrowing of the artery lumen. Cr(VI) inhibited trophoblast cell invasion into the uterine-fetal interface. To conduct the current project, timed pregnant rats (8-10 wk of age) will be divided into four experimental groups: Control (n=10), Cr(VI) - 0.1 ppm (n=10), Cr(VI) - 1.0 ppm (n=10), and Cr(VI) - 5.0 ppm (n=10), and exposed to respective doses of potassium dichromate (Cr(VI)) from GD 9.5 to 12.5 and euthanized on GD18.5. AIM-1 will determine the placental and fetal weight, resorption sites, the number of male and female pups, placentas shape, and live and dead pups. Effects of Cr(VI) exposure on spatio-temporal expression of signaling molecules in regulating trophoblast invasion. AIM-2 will identify the mechanism of Cr(VI) on the myogenic response of the uterine main artery and its extracellular matrix. Uterine main arteries will be dissected from the pregnant rats treated with Cr(VI). The contractile responses, endothelial-dependent relaxation responses, active pressure responses, internal and external diameter, wall thickness, cross-sectional area, and wall strain will be calculated using pressure and wire myographs. In Study 2b, the extracellular matrix (ECM) proteins network of the uterine artery will be determined. The current study is innovative to fill the gap in understanding the role of Cr(VI) in altering uterine vascular adaptation during pregnancy. These findings will help regulate Cr(VI) exposure in pregnant women since they are vulnerable to EDCs’ exposure.

项目概要 据国家统计局称，美国是世界领先的铬化合物生产国之一。 自来水质量数据库和环境工作组报告显示，美国约 7400 万人几乎 7,000 个社区饮用被六价铬 (Cr(VI)) 污染的水，他们很容易 各种健康问题，包括不孕、早产、早产、胎儿宫内生长 使用新生儿医院记录中发布的数据进行了一项研究。 来自加利福尼亚州威利茨的孕妇首次接触六价铬，对生殖产生不健康的影响。 美国报告了人类女性及其婴儿非职业性 Cr(VI) 暴露的情况。我们的研究 涉及人类胎盘的研究报告称，足月胎盘中 Cr 的积累之间存在正相关性（来自 密歇根州女性）和氧化应激增加然而，Cr（VI）如何导致胎盘发育异常， 子宫螺旋动脉在很大程度上被重塑以提供足够的血液。 向发育中的胎儿供应母体血液和营养物质。子宫螺旋动脉重塑异常。 目前的研究表明 Cr(VI) 会破坏子宫螺旋动脉重塑。 首先通过抑制滋养层细胞侵袭和改变生长因子介导的信号通路。 当时，我们的初步研究表明 Cr(VI) 引起子宫动脉壁增厚和狭窄 Cr(VI) 抑制滋养层细胞侵入子宫-胎儿界面。 项目中，定时怀孕大鼠（8-10周龄）将被分为四个实验组：对照组（n=10）、Cr(VI) - 0.1 ppm (n=10)、Cr(VI) - 1.0 ppm (n=10) 和 Cr(VI) - 5.0 ppm (n=10)，并暴露于相应剂量的 GD 9.5 至 12.5 的重铬酸钾 (Cr(VI)) 并在 AIM-1 上安乐死将确定。 胎盘和胎儿的重量、吸收部位、雄性和雌性幼崽的数量、胎盘形状以及活体和 Cr(VI) 暴露对调节信号分子时空表达的影响。 AIM-2 将确定 Cr(VI) 对子宫主肌生成反应的机制。 将从经处理的怀孕大鼠中解剖子宫主动脉及其细胞外基质。 Cr(VI)。收缩反应、内皮依赖性舒张反应、主动压力。 将计算响应、内径和外径、壁厚、横截面积和壁应变 在研究 2b 中，使用压力和线肌动描记器观察子宫的细胞外基质 (ECM) 蛋白网络。 目前的研究具有创新性，填补了了解 Cr(VI) 在动脉中的作用的空白。 这些发现将有助于调节妊娠期间的子宫血管适应。 孕妇，因为她们容易接触 EDC。